Lipid replacement therapy (LRT) has been used along
with other strategies, such as antioxidant therapy, to replace
damaged or oxidized cellular lipids that accumulate during
aging and in various clinical conditions. Differing from traditional
lipid nutritional supplementation, LTR replacement
lipids are protected from oxidation and damage during storage,
ingestion and digestion. Important lipids that require
constant replacement are phospholipids, glycophospholipids
and other lipids that make up cellular and organelle
membranes, especially mitochondrial membranes.

Decreased mitochondrial function and loss in the efficiency
of the electron transport chain are related to aging and
fatigue. Oxidative damage to mitochondria, mainly from
Reactive Oxygen Species (ROS), results in peroxidation of
cellular and mitochondrial lipids, proteins and DNA, but it
is ROS damage to mitochondrial membrane lipids that may
cause the most rapid loss of mitochondrial function. LRT
along with antioxidants can circumvent ROS membrane
damage and replace and restore mitochondrial and other
cellular membrane functions via delivery of replacement
lipids in their unoxidized, undamaged states.

Recent clinical trials have shown the benefit of LRT plus antioxidants in
restoring mitochondrial electron transport function and
reducing fatigue. In aging subjects mitochondrial function
was restored to levels found in young adults in consort with
reductions in fatigue, suggesting the anti-aging and antifatigue
benefits of LRT plus antioxidants in protecting
mitochondrial and other cellular membranes from oxidative
and other damage and preventing loss of function.

INTRODUCTION

The use of natural lipids for dietary support and even
therapy for various medical conditions has a long and rich
history and will not be dealt with in this brief commentary.

Instead I will concentrate on discussing recent clinical trials
that have shown the effectiveness of lipid replacement
therapy (LRT) plus antioxidants in the treatment of certain
clinical disorders and conditions as well its use in antiaging
supplements. LRT is not just the dietary substitution
of certain lipids with proposed health benefits; it is the actual
replacement of damaged cellular lipids with undamaged
lipids to ensure proper structure and function of cellular
structures, mainly cellular and organelle membranes. This
constitutes the most important functional use of lipids in
our bodies. Damage to membrane lipids can impair fluidity,
electrical properties, enzymatic activities and transport
functions of cellular and organelle membranes.1-3

An important difference between simple lipid dietary
supplementation and LRT is that the lipids in LRT must be
protected from oxidative and other damage during storage
and during the ingestion, digestion and absorption processes
in vivo. Thus LRT should result in delivery of high concentrations
of unoxidized, undamaged lipids, and this is
important in reversing the damage and restoring function to
(partially oxidized) cellular membranes. Combined with
antioxidant supplements, LTR has proven to be an effective
method to prevent aging-associated changes in certain cellular
activities and functions and for use in the treatment of
certain clinical conditions.

n-3 LIPID SUPPLEMENTS AND CHRONIC
ILLNESSES

In the past several years different sources of lipid
dietary mixtures have been used to improve general health
or for more specific uses, such as in the treatment of cardiovascular
diseases and inflammatory disorders.4-10

Although not every clinical study has found health benefits
from supplementing specific lipids in the diet,7,11 most studies
have documented the value of dietary supplements that
favor certain types of lipids over others. The most common
substitution is the dietary administration of lipids where n-
3 polyunsaturated fatty acids (mainly fish- or flaxseedderived)
are favored relative to n-6 lipids.4-10

Oral administration of n-3 polyunsaturated fatty acids has
been beneficial in various clinical conditions. This includes
reduction in risk of coronary heart disease11-14 and death due
to cardiac arrest,15-17 age-associated macular degeneration,18
asthma,19 ulcerative colitis,20,21 Crohn’s disease,22 IgA
nephropathy,23,24 rheumatoid arthritis,25,26 diabetes mellitus,
27,28 various malignancies29,30 and other conditions.

Discrepancies and conflicting results in some clinical studies
on the health benefits of n-3 polyunsaturated fatty acids could
be the result of insufficient care in the storage, preservation,
dose and administration of the dietary lipid mixtures.31

INGESTED LIPIDS ARE QUICKLY ADSORBED AND
TRANSPORTED TO TISSUES

Lipids such as those found in various cellular compartments
are in dynamic equilibrium in the body, and this is
why LRT is possible. Orally ingested lipids diffuse to the
gut epithelium and are bound and eventually transported
into the blood and lymph using specific (carrier alipoproteins)
and nonspecific (partitioning and diffusion) mechanisms. 32-34

Within minutes, lipid molecules are transported
from gut epithelial cells to endothelial cells, then excreted
into and transported in the circulation bound to lipoproteins
and blood cells.34,35 Once in the circulation, specific
lipoprotein carriers and red blood cells protect lipids
throughout their passage and eventual deposition onto specific
cell membrane receptors where they can be taken into
cells via endosomes and by diffusion.36 Inside the cells,
lipid transporters deliver specific lipids to cell organelles
where they are taken in by specific transport proteins and by
partitioning and diffusion.37 Once undamaged lipids such
as phosphotidylethanolamine are transported to mitochondria,
they can be used to synthesize other lipids, such as
phosphotidylserine.

This system works efficiently, probably
due to the concentration gradients that exist from the gut
during the digestion of lipids to their absorption by gut
epithelial cells and their transfer to the blood, to the tissues,
and ultimately to the cells’ interior. Damaged lipids can be
removed by a similar reverse process that may be driven by
lipid transfer proteins and by enzymes that recognize and
degrade damaged lipids.38

FATIGUE, AGING AND OXIDATIVE DAMAGE TO
MITOCHONDRIA

Many medical conditions are associated with fatigue,
including respiratory, coronary, musculoskeletal, and bowel
conditions as well as various cancers and infections.39,40
Chronic fatigue (intractable fatigue lasting more than 6
months that is not reversed by sleep) is the most common
complaint of patients seeking medical care.41,42 It is an
important secondary condition in many clinical diagnoses,
often preceding and is related to patients’ diagnoses.42,43 The
phenomenon of fatigue has only recently been defined as a
multidimensional sensation, and attempts have been made to
determine the extent of fatigue and its possible causes.40,43

Most patients understand fatigue as a loss of energy and
inability to perform even simple tasks without exertion.
Using the Piper Fatigue Scale measurement tool that combines
multiple fatigue-associated elements into an overall
score fatigue has been quantitated as a multi-component sensation.40,43

We have successfully used the Piper Fatigue Scale
in clinical studies on aging subjects who complain of fatigue
to determine their responses to LRT plus antioxidants.44,45
The complex phenomenon called fatigue is involved
with cellular energy systems found primarily in the mitochondria.

Damage to cellular mitochondria can impair the
abilities of cells to produce high-energy molecules, such as
ATP and NADH. This occurs naturally with aging and during
chronic illness, mainly by the build up of damaged
mitochondrial components that impair function. During
aging the production of Reactive Oxygen Species (ROS),
made up of oxidative and free radical oxygen- and nitrogencontaining
molecules, such as nitric oxide, oxygen and
hydroxide radicals and other molecules, can cause oxidative
stress and cellular damage, resulting in oxidation of lipids,
proteins (enzymes) and DNA.

Once oxidized, these cellular
molecules are structurally and sometimes functionally
changed. Major targets of cellular ROS damage are mitochondria
and nuclei, mainly their phospholipid/protein
membranes and DNA.3,46-49

Damage to the former results in
alterations in membrane fluidity and electrical properties, whereas damage to protein enzymes and deletions or modifications
in DNA structure can result in alterations in
enzyme activities and gene expression.

Mitochondria themselves produce some ROS as a consequence
of oxidative phosphorylation,50 but excess ROS
production throughout our lifetimes can result in accumulation
of mitochondrial and nuclear damage. To counter this,
cellular free-radical-scavenging enzymes neutralize excess
ROS and repair enzymes reverse ROS-mediated damage.50

Although some ROS production is important in triggering
cell proliferation, gene expression and destruction of invading
microbes,51 with aging, ROS damage accumulates
because antioxidant enzymes and enzyme repair mechanisms
along with biosynthesis cannot restore or replace
enough ROS-damaged molecules.3,46,47 Disease and infection
can also result in similar damage that exceeds the abilities
of cellular systems to neutralize, repair, or replace
damaged molecules.3,50

Mitochondria from aging animals show higher levels of
accumulated ROS damage to mitochondrial membranes,
enzymes and DNA than found in young animals.3,51 At the
molecular level, damage to phospholipids and other lipids in
mitochondrial membranes by ROS free-radicals can affect
membrane integrity, fluidity and transmembrane electrical
potentials, resulting in damage to the electron transport
chain and its associated components and loss of function.3,50

Young cells and organisms can cope with ROS since they
possess high levels of free-radical scavenging systems that
neutralize ROS, such as superoxide dismutase and glutathione
reductase. They also have a higher capacity to
repair or replace damage caused by ROS. With aging these
homeostatic systems naturally decline and can be overwhelmed
by ROS and oxidative stress.51,52 Since the aging
process results in mitochondria accumulating ROS damage
to their membranes, enzymes and DNA, this is thought to
contribute to or even be a cause of the aging process.3,47,51-53

MANAGING ROS-MEDIATED DAMAGE WITH
ANTIOXIDANTS

Reducing cellular and mitochondrial membrane and
DNA damage and loss of membrane integrity are important
in preventing loss of cellular energy and regulating cellular
life span.3,54 This can be done, in part, by neutralizing ROS
with various antioxidants or increasing free-radical scavenging
systems that neutralize ROS. Dietary antioxidants
and some accessory molecules, such as zinc and certain vitamins,
are important in maintaining free-radical scavenging
systems, biosynthetic capacity, membranes, enzymes and
DNA. There are at least 40 micronutrients required in the
human diet,55 and aging increases the need to supplement
these in a normal diet to prevent age-associated declines in
mitochondrial and other cellular functions.

Although very important, antioxidant use alone may not be sufficient to
maintain cellular components free of ROS damage. This is
why LRT is important in replacing ROS-damaged lipids
along with antioxidant use to prevent further oxidation.

In animal studies the effects of reducing ROS have
been dramatic in aging and disease models. For example,
in rodents there are age-dependent losses in antioxidants
and antioxidant vitamins as well as reductions in glutathione
and levels of antioxidant enzymes.56 In an aged rat
study, the effects of alpha-lipoic acid and other dietary
antioxidants on the levels of cellular antioxidants, such as
reduced glutathione and vitamins C and E, levels of mitochondrial
membrane lipid peroxidation and activities of
mitochondrial electron transport and accessory enzymes,
have been investigated and found to decrease but not eliminate
ROS damage to the electron transport chain.57

Thus dietary antioxidant supplementation partially reversed the
age-related declines in cellular antioxidants and mitochondrial
enzyme activities and prevented mitochondria from
most age-associated functional decline. In another study
rats were fed diets supplemented with coenzyme Q10,
alpha-lipoic acid, melatonin, or alpha-tocopherol for a sixmonth
period. They found that the antioxidant mixture
could inhibit the progression of certain age-associated
changes in cerebral mitochondrial electron transport chain
enzyme activities.58,59 Thus animal studies have shown that
antioxidants can prevent, at least in part, age-associated
changes in mitochondrial structure and function.

However,
antioxidants alone cannot completely eliminate ROS damage
to mitochondria, and this is why LRT is an important
adjunct to antioxidant administration.
In addition to the aging-associated oxidative changes in
mitochondrial enzymes and lipids, mitochondrial DNA also
accumulates oxidative damage during the aging process.3,51-
54,60,61

To prevent this, antioxidants have also been useful,
such as vitamins C and E, coenzyme Q10, sulfur-containing
antioxidants and plant antioxidant extracts.62,63 Age-associated
damage to mitochondrial DNA may affect their ability
to function due, in part, to a loss in ability to synthesize and
replace critical mitochondrial enzymes.

Antioxidants may also affect the pathogenic processes
of certain diseases.50,60 The experimental dietary use of
antioxidants can prevent age-associated mitochondrial dysfunction
and damage, inhibit the age-associated decline in
immune and other functions and prolong the lifespan of
laboratory animals.3,56-59,63,64

ANIMAL STUDIES USING LIPID REPLACEMENT
THERAPY AND ANTIOXIDANTS

Another method used to reverse damage to tissue membranes
is to replace damaged cellular and mitochondrial
membrane phospholipids and other lipids using dietary supplements
containing polyunsaturated phosphatidylcholines
and other phospholipids, glycophospholipids and fatty acids that are essential structural and functional components of all
biological membranes.44,45 One such LRT dietary supplement
is called NT Factor,™ and it has been used successfully in animal
and clinical lipid replacement studies. Its encapsulated
lipids are protected from oxidation in the gut by the inclusion
of antioxidants and can be absorbed and transported into tissues
without undue damage.44,45 NT Factor contains a variety
of components (Table 1), including glycophospholipids and
other lipids, antioxidants, nutrients, probiotics, vitamins, minerals
and plant extracts.44

NT Factor has been used to produce an anti-aging
effect in aged laboratory animals. In 18- to 20-month-old
rats, Seidman et al65 found that NT Factor prevented hearing
loss associated with aging and shifted the threshold
hearing from 35-40 dB in control aged animals to 13-17 dB
in the NT Factor group. These results were highly signifi-
cant (p<0.005). They also found that NT Factor preserved
cochlear mitochondrial function as measured in a
Rhodamine-123 transport assay, increasing mitochondrial
function by 34%.

In these experiments, Rhodamine-123 is
transported into mitochondria where it is chemically
reduced to its fluorescent form only under conditions where
mitochondria are fully functional.66 NT Factor also prevented
a common aging-related mitochondrial DNA deletion
(mtDNA4834) found in the cochlear of aging rats.65

Thus LRT plus antioxidants was successful in preventing
age-associated hearing loss and mitochondrial damage in an
animal model for aging.

CLINICAL STUDIES USING LIPID REPLACEMENT
THERAPY AND ANTIOXIDANTS

LRT plus antioxidants has been successfully used in
clinical studies to reduce fatigue and protect cellular and
mitochondrial membranes from damage by ROS. For example,
NT Factor has been used in a vitamin and mineral mixture
(Propax™) in cancer patients to reduce the effects of
cancer therapy, such as chemotherapy-induced fatigue, nausea,
vomiting, and other side effects associated with
chemotherapy.67 In a twelve-week double-blinded, crossover,
placebo controlled, randomized trial on cancer patients
receiving chemotherapy, Propax supplementation resulted in
improvement from fatigue, nausea, diarrhea, impaired taste,
constipation, insomnia and other quality of life indicators.67

The majority (64%) of the patients in this study reported significant
reductions in chemotherapy-induced side effects,
and 29% experienced no overall worsening of chemotherapy
side-effects. Following cross-over to the supplement
containing the Propax, patients reported rapid improvement
in nausea, impaired taste, tiredness, appetite, sick feeling
and other indicators associated with chemotherapy.67

We have used Propax plus NT Factor in an LRT study
with severely fatigued, aged subjects (>60 years-old) with a
variety of clinical diagnoses to reduce fatigue, as measured
by the Piper Fatigue Scale.40,43 We found that fatigue was
reduced approximately 40%, from severe to moderate
fatigue, after eight weeks of using Propax containing NT
Factor. The results were highly significant (p<0.0001).45

A more recent LRT plus antioxidant study was initiated to
examine the effects of NT Factor on fatigue in moderately
and mildly fatigued subjects and to determine if their mitochondrial
function, as measured by the transport and reduction
of Rhodamine-123, and fatigue scores improved with
administration of NT Factor.44 Using NT Factor for eight or
twelve weeks resulted in a 33% or 35.5% reduction in
fatigue, respectively. The results were highly significant
(p<0.001) and were obtained using the Piper Fatigue Scale
for measuring fatigue.44

In the LRT/antioxidant trial with moderately fatigued
patients, reductions in fatigue paralleled significant gains in
mitochondrial function.44 In fact, there was good correspondence
between reductions in fatigue and gains in mitochondrial
function. After only eight weeks of NT Factor,
mitochondrial function was significantly improved
(p<0.001). Interestingly, after twelve weeks of NT Factor
use, mitochondrial function was found to be similar to that
of young, healthy adults.44 After twelve weeks of NT Factor
use, subjects discontinued the supplement for an additional
twelve weeks, when their fatigue and mitochondrial function
were again measured. After the twelve-week wash-out
period, fatigue and mitochondrial function were intermediate
between the initial starting values and those found after
eight or twelve weeks, indicating that continued use of the
supplement is probably required to maintain lower fatigue
scores and show improvements in mitochondrial function.44

The results indicate that LRT/antioxidants can significantly
improve and even restore mitochondrial function and
improve fatigue scores in aging human subjects.

CHRONIC FATIGUE, MITOCHONDRIAL FUNCTION
AND DEGENERATIVE DISEASE

When mitochondrial function is impaired, the net energy
available to cells is limited to the Krebs Cycle and anaerobic
metabolism. There are a number of conditions and
substances that can impair mitochondrial function,45,46,54
but oxidation and damage of mitochondrial lipids in membranes
are thought to be among the most important causes.
3,54,68 Oxidation of membrane lipids results in modification
of membrane fluidity and the electrical potential barrier
across mitochondrial membranes, essential elements in
the proper functioning of the electron transport chain.3,54,68

Mitochondrial function appears to be directly related to
fatigue, and when patients experience fatigue their mitochondrial
function is inevitably impaired. Fatigue is a complex
phenomenon determined by several factors, including
psychological health. At the biochemical level fatigue is
related to the metabolic energy available to tissues and cells.

Thus the integrity of cellular and intracellular membranes,
especially in the mitochondria, is critical to cell function
and energy metabolism. When mitochondrial membrane
glycophospholipids, phospholipids, fatty acids, and other
essential lipids are damaged by oxidation, they must be
repaired or replaced in order to maintain the production of
cellular energy to alleviate fatigue.

The decline of cellular energy production with aging
appears to be due, in part, to mitochondrial lipid peroxidation
by ROS and the failure to repair or replace damaged molecules
at a rate that exceeds their damage. Membrane damage
and subsequent mitochondrial dysfunction by ROS can also
lead to modifications (especially mutations and deletions) in
mitochondrial DNA (mtDNA). The mitochondrial theory of
aging proposes that the development of chronic degenerative
diseases is the result, in part, of accumulated mtDNA mutations
and deletions and oxidative damage to mitochondrial
membranes over time.3,54,61,68,69

Indeed, these studies have
linked the development of certain chronic diseases with the
degree of mitochondrial membrane lipid peroxidation and
mtDNA damage. Thus the damage to mtDNA and mitochondrial
membranes seems to be involved in the etiology of
age-associated degenerative diseases leading to changes in
the expression of genes important for cell survival as well as
those that control aging.69 Restoration of mitochondrial
membrane integrity, fluidity and other properties are essential
for the optimal functioning of the electron transport chain
and oxidative generation of ATP and NADH.

Declines in
energy production with aging and disease coupled with
increases in oxidative stress can change gene expression programs
and activate cellular apoptosis programs.70 Apoptosis
can also be attenuated with the administration of n-3 polyunsaturated
fatty acids.71

The ability to control membrane lipid peroxidation and
DNA damage likely play a major role in the aging process
and the development of age-related degenerative diseases.
3,60,72 LRT has proven to be a valuable tool in helping
maintain mitochondrial function, and along with combined
antioxidant use LRT should be an important part of antiaging
strategies as well as strategies used to treat various
age-associated degenerative diseases and conditions.

NT Factor is a nutrient complex that is extracted and prepared using a proprietary process.
In addition, nutrients, vitamins and probiotic microorganisms are added to the preparation.
It contains the following ingredients: